ABSTRACT Symptomatic knee osteoarthritis (OA) affects more than 10 million individuals in the United States and is a leading cause of disability and medical costs. However, there is now a critical shortage of treatment options for people with KOA because comorbidities that complicate treatment selection are highly prevalent in this population. Recent studies indicate that blockade of the genicular nerve may be efficacious for OA knee pain, with benefit of 3 months or more. This treatment could theoretically be very helpful in managing knee OA pain in selected patients. However, those studies were limited by methodologic issues (e.g. small size, short duration),most omitted objective outcome measures, and only two used a sham control. It is also unclear whether the widely-used ?prognostic? block has clinical utility. While all reported favorable safety, adverse event reporting was generally non-systematic and, in particular, did not evaluate for longer term structural consequences in the knee. The latter is of concern because of the well-known precedent of neuropathic arthritis. Therefore, there is a need to better understand the biomechanical implications of sensory nerve blockade around a knee and the short- and long-term effects on articular structures. Understanding these aspects will predicate development of a risk mitigation strategy while preserving the therapeutic benefit of RFA. The goal of this R34 is to complete logistical preparation for a one-year sham-controlled, randomized controlled trial (RCT) of RFA for KOA assessing PROs including average daily pain (primary), patient-acceptable symptom state, treatment failure; objective measurement of physical function, activity, proprioception, joint loading using gait analysis and mobile devices, and knee structure using MRI. The primary endpoint will be at 3-months, with secondary endpoints at 6, 9 and 12 months. Planning activities will include deciding between two compelling candidate designs, which allow testing of the value of the ?prognostic block?: ?Efficacy And Effectiveness Too? (EE2) versus Factorial design. Additional unique aspects will include analyses of biologically-relevant variables (sex, widespread pain, unilateral versus bilateral KOA). We will utilize stakeholder and scientific advisory committees to evaluate the relative merits and feasibility of the candidate RCT designs, plan the study interventions, define outcome measures and targets, and finalize sample size projections and analytic plan. We will write the consent materials, and obtain ethical and regulatory approval. We will construct electronic source documents and a data capture system (REDCap) with query and reporting functions. We will assemble the teams and collaborations necessary to administer the interventions, conduct trial activities, monitor data quality and safety, putting in place subcontracts where appropriate. We will finalize development of a mobile application for frequent collection of patient-centered outcomes in the context of daily life. The results of this work will predicate the final design of the future clinical trial, with a U01 application anticipated in 2022.